Download CH 6 High Risk Populations - J. de Hoon

1st Master Biomedical Sciences
Pharmaceutical Medicine
Exam questions 2014
Questions of which 2 will be part of the examination:
Ch1. Drug Design and Discovery – J. Thomas
1. Drug discovery and design: which selection criteria determine the choice of a project for the
development of a new compound?
Strategic: Is it desirable to do it? Does it have to be done? Will we profit?
Market prediction (future prospects, opportunities and threats)
unmet medical need (Gap between ideal and reality, look in the future)
company strategy and competencies (strengths and weaknesses)
Scientific and technical: Can it be done? Is it feasible? Available proteins, assays, animal
models, …
Scientific opportunity: scientific base, room for innovation?
Competitive advantage: First-in-class, Fast follower, me too, …
Expected difficulties: endpoints? Acute or chronic? Life threatening?
Patent protection
Operational: Can we do it? Work with other company?
Necessary resources: Staff and expertise, facilities, capital, equipment, ….
Timescale & planning?
 Decision by management based on all elements
2. Discuss the role of pharmacochemistry in drug discovery and design.
Lead finding
- Screening
HTS of chemical libraries
Computerized – miniaturized -> biochemical and cellular effects
Combinatorial chemistry (combining (protein) building blocks)
- De Novo design = Computer Assisted Drug Design (CADD)
Ligand based:
improvements of endogenous L
development of synthetic L: Pharmacophore model (hydrophilic + hydrophobic)
Target Based:
Docking of small molecules in 3D structure of target
(X-ray Christalography or NMR spectroscopy)
Lead optimization:
- Improve the biological activity: selectivity, strength, safety
- Variables: PK, stability,Patents, formulations, genotoxicity, chirality, ease of synthesis, …
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3. Drug discovery and design: which criteria determine the choice of a candidate drug for further
non-clinical and clinical development?
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Selectivity and strength for Target
Appropriate PK (ADME)
Pharmacological activity (in vivo and In Vitro functioning
Safety profile
Chemically stable (in formulation)
Large scale production and patent protection possible?
Ch2. Pharmaceutical Development – G. Van den Mooter
API = Active Pharmeceutical Ingredient – Drug Substance
Drug Product = API + excipients
Excipient = inactive compounds that allow administration and formulation, Bulk formation
(core+coating)
4. Provide an overview of the physicochemical aspects which are part of the pre-formulation
phase of a drug.
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Solubility => BCS classification
Determines the formulation strategy, Poor solubility can still have good bioavailability
Influences of pH, buffers, organic solvents, ionic strength -> High-throughput analysis
Increasing solubility: Cosolvents, complexing agents (cyclodextrins encapsule non-soluble
parts), surfactants & polymers
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Intrinsic Dissolution rate = Absortion window: where and when
Rate at which an API concentration can be obtained -> Bioavailability and stability
=ΔC. (D.A/V.d)
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Ionisation => effect on bioavailability
Determine pKa -> change pH to improve solubility or salt formation
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Partition Coefficient = LogP
Indication of Lipophilicity/hydrophobicity => absorption (80% by passive diffusion)
Partitioning solvent changes LogP (mostly n-Octanol)
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Solid state properties
Crystaline = preferential 3D arrangement, thermodynamically stable (melting point), phase
transition
Amorphous = chaotic arrangement and unstable, glass transition –> change in baseline
of thermogram, higher solubility and dissolution rate
Differential Scanning Calorimetry = Quantification of heat production and uptake ->
Thermogram (dq/dt) C -> uptake of heat; A -> shift in baseline
X-ray diffraction: C -> Bragg reflections (positive interference), A -> Halo Pattern
Polymorphisms (different lattice) in solid state: conformational or stacking
Pseudopolymorphisms (solvents in lattice) => intermolecular interactions determine
bondings strength
 change physicochemical properties => most stable form needed!
Dynamic Vapour Sorption analysis: uptake off water can influence stability
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Stability is influenced by:
Solid state : Heat, light and water
Solution: Heat, light, pH and extreme acidic, basic or oxidizing environment
Compatibility with excipients and packaging
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5. Provide an overview of the biopharmaceutical aspects which are part of the pre-formulation
phase of a drug.
Permeability – absorption potential
- Parallel artificial membrane permeation assay (multi-well)
No animals, HT, inexpensive
Only passive diffusion, dependent on pH and lipid composition
- CaCo cultures: Human colon adenomacarcinoma
Erythrocyte Monolayer with TJ, Active transports, brush border enzymes
Human, evaluation of toxicity, transport and absorbtion
No mucus and static model
6. What kind of compounds (API and excipients) can be part of a tablet?
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API
Filler/diluents: reach correct weight ex cellulose
Binder: keep everything together ex. Starch or cellulose derivatives
Desintegrant: desintegration at correct location (contact with GI fluids) ex. Cross-linked
polymers or starch
Wetting agent: improve contact between aqueous environment and compound ex
polysorbate-80
Flow promotor: for homogenous dosing ex. Colloidal SiO2
Lubricant: decrease friction during manufacturing ex Mg-Stearate
7. What does “an oral controlled drug delivery system” refer to? What are the advantages and
disadvantages of these systems?
Systems that enable continuous release of the API in the GI tract during a specified time.
Release kinetics are reliable and reproducible.
Systems that enable a controlled residence time of the dosage form or release at a specific
site in the GI tract to obtain a specific or local effect.
+ reduced intake and side effects
- Dose dumping
+ better compliance and comfort
- Difficult to remove toxic dose
+ less fluctuation
- More expensive
8. What kind of strategies can be used to make oral controlled drug delivery systems?
Reservoir systems:
- Polymer coating (insoluble, slowly dissolving or pH-dependent) ex. Ethylcellulose
=> rate controlling membrane ex. Cellulose derivatives (pores)
- Layered system: API 1 - polymer - API 2 (slow release) - inert core
- Pulsed release: 3 layers of API released at different time points
Matrix Systems
- Insoluble matrix: diffusion of API ex. ethylcellulose
- Erodable or slowly dissolving: API is released because of erosion
Hydrophilic matrix ex. Cellulose Acetate Pallidium
Lipophilic matrix ex. Glycerylmonostearate
Bioadhesion: Buccal tablet stays on gingiva and is slowly absorbed ex. Polyacrilyc acid
<-> gels
Osmosis: Osmotically active core, push compartment and membrane with hole.
API is pushed out when polymer swells
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9. Which elements need to be taken into account during the pharmaceutical development of
suspensions, creams and ointments?
Suspenisons = Solid dispersed in liquid
- For insoluble or instable APIs, when liquid is desired
- Difficult homogenous dosing: wetting agent, increasing viscosity, adequate particle size
- Stability: Caking = interaction at secondary minimum -> structured medium, electrostatic
and sterical stabilisation
Creams = water and oil phase
- Emulsifiers to maintain stability, viscosity increasing, moisturizers, penetration enhancers
- Production by applying energy
Ointments = No water
- Ointment base (ex. vaseline)
- Surfactant, fragrances, perfumes
Ch3. Clinical Drug Development – J. de Hoon
Clinical research = improve knowledge of disease or treatment, scientifically sound and
ethically acceptable, in humans
Clinical Trial = evaluate efficiency and safety of medicinal products
IND file = Investigational new drug file: all data obtained for molecule in non-clinical test
Mode Of Action , safety, …
IB = Investigators brochure, IND + info from clinical trials
RCT: Randomized Controlled Trial
Clinical Endpoint: describes how a patient feels, functions, survives
Hard vs Soft ; Primary vs Secondary
Needed for approval
Surrogate Endpoint: as predictor for Clinical endpoint, Therapy induced changes
Biomarker: objectively measured characteristic for therapy induced changes and response
Benefit vs risk
10. Discuss the principles taken into account when calculating the MRSD for conducting a FIM
trial.
MRSD = Maximal Recommended Starting Dose
FIM trial = First-in-Man or Phase I trial
NO(A)EL = No Observed (Adverse) Effects Level
HED = Human Equivalent Dose
MABEL = Minimal Anticipated Biological Effect Level (NOEL)
MED = Minimal Effective Dose
PAD = Pharmacological Active Dose
Toxicological approach
NOAEL based on animal studies (mg/kg) => convert to Human Equivalent Dose
Small animals: more efficient metabolism, larger body surface
HED from most appropriate/sensitive species
Divide by safety factor (default = 10) -> MRSD
Conservative approach
MABEL: Lowering the dose even further when Biological effect is expected
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11. Phase I and phase II RCTs: discuss.
Exploratory Phase
Phase I: Initial safety trial
- in healthy male volunteers (exceptionaly on patients, ex oncology)
- without therapeutic objectives: Safety, tolerance and PK, 6-12m
- Single/multiple ascending dose (PK)
- After phase II: Bio-equivalence, interaction & QT studied
- Alternatives: microdosing, Proof-of-Concept, eCTA, translational models
- Small groups: descriptive statistics
Phase II: First into target population
- Evaluate efficacy and safety in small group of patients, no intent to treat
- Tolerance, PK & PD, 12-24 months, male and female
- Target validation: Proof-of-Concept/Principle
12. Phase III RCTs: discuss.
Confirmatory phase
- Confirming efficacy and safety in a larger patient population
- New Drug Application => while waiting for Approval
- Confirm indications and dosing, 2-7y
- Investigate High risk population
- Superiority Trial: to detect a difference between treatments
Equivalence Trial: to confirm the absence of a difference
Non-inferiority trial: to show that the new treatment is at least as effective as...
13. RCT and trial design: cross-over versus parallel group design. Discuss.
Golden standard but expensive, prospective
- Patients randomly assigned in active and control group
- Controls: Placebo, best available treatment, nothing, dose-response, historical data, …
Parallel group
- Progress together in time
Cross-over study
- After wash-out period -> Patients change groups
- All patients receive both treatments
- Less variation, less subjects
- Not for fast evolving diseases, might not go back to baseline
- Chronic diseases
14. Discuss “internal” versus “external” validity in the context of clinical trials.
Internal validity
- Was the trial executed in a scientifically correct way? Prevention of bias and confounding:
Randomization, Blinding (single,double, triple,…), Placebo vs Nocebo
Best available treatment
External validity
- Can results be extrapolated to all patients in the “real” world?
- Selection criteria limit the sample -> artificial
- Too few, too narrow, too average-aged, too short
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CH 4 Biologicals and Biosimilars – P. Declerck
15. Provide an overview of the production process of biological
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Cloning: plasmid and DNA strand ligated -> transfection
Cell line expansion: cell cultures or bioreactors -> monitor conditions
Protein expression: recovery through centrifugation and filtration
Purification, characterization and stability
Controls: check for mutations, correct configuration
Back-up: Sample in liquid Nitrogen
16. What are the most important differences between “small molecules” and “biologicals”.
Small molecules
- Chemical synthesis
- Defined structure
- Relatively stable
- Less sensitive to changes in process
- Not immunogenic
Biologicals
- Produced by living system, cell cultures
- complex biomolecule: Heterogenous structure <- cell type and culture/external conditions
- Variable, sensitive to conditions
- Extremely sensitive to changes
- Immunogenic: also dependent on production process, handling, …
17. What are “biosimilars”? Why was this concept introduced? What is the difference between a
generic (small molecule) drug and biosimilars?
Biosimilar: Copy of an already authorized biological product claimed to be similar in quality,
safety and efficacy, Comparability exercises and guidelines (quality and clinical) (since 2006)
Why? New product developed -> approved and Patented
Patent expires: several companies start to produce same protein -> never identical
 Physicochemical properties, impurities and clinical properties
 Centralized procedure for assessment by EMA (CHMP)
 WHO: Naming of drugs -> International Non-proprietary Names
Difference? Small molecules will always be the same independent of production process. Even
pure protein will still contain many variants (glycosylation, oxidization, deamination,…)
Interchangeability needs to be proven, Diverge over time, biosimilars not compared to eachother
CH 5 Study design – J. De Hoon
18. Give an overview of the different kinds of study design which are being used in clinical
research and in pharmaco-epidemiology. What are their respective advantages and
disadvantages?
Observational - Descriptive
- Case Report: challenge – dechallenge – rechallenge (only if mildly toxic)
1 unusual observation -> hypothesis generating
Cheap and easy but little causality, and no hypothesis testing
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Case series: pooling of cases -> estimate incidence (No control!)
Observational - Analytical
- Case-Control Trial – Retrospective
Select cases and controls => Look for previous exposures => Odds ratio
+ Multiple exposures, rare and late responses
- Sensitive to bias and confounders
- Cohort study – Prospective, retrospective and ambispective
Follow an exposed group over time => Incidence/hazard ratio
+ Multiple responses and rare events
- Large groups and Bias, long duration
Experimental – Analytical
- RCT
+ Powerful statistics and control for confounders
Many limitations: nr of patiets, exposure, follow up time
- Ethical issues, expensive, External validity
Registering before start -> Ethical approval
- Meta-analysis
Systematic review of several studies of same drug -> Publication bias
Large Power!
CH 6 High Risk Populations - J. de Hoon
19. Why are the elderly a high risk population for the use of drugs?
High risk and also more drug use
Slow metabolism, Los of functional units: Alveoli, nefrons, hepatocytes
Absorption
- Decrease stomach fluids – decreased acidity – decreased solubility
- Decreased first-pass metabolism: larger bioavailability or less activation
o Important for ASA, propranolol, lidocaine, Lecodopa, …
Distribution
- Decreased Extravascular fluids
o Polar drugs: smaller Vd -> increased CP -> lower Dose
o Non-polar drugs: larger Vd -> Longer T1/2 -> fewer intakes
Reduced clearance
- Liver:
o Accumulation of drugs with a high extraction ratio
o Increased sensitivity for narcotics, antidiabetics, anticoagulantia, …
- Kidney:
o Accumulation water soluble drugs: diuretics, ACE inhibitors, …
o Failure has effect on Liver Cl
20. Discuss the use of drugs during pregnancy and lactation.
Pregnancy
- Mother comes first, try not to risk the baby
- Should not use Drugs -> Local treatment
- Adjust treatment: Historically safe
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Lactation
- Less risks – only small amounts go to baby
- Except hypnotics & sedatives
- Prevent lactation: diuretics, estrogen,…
Chronic illness
- Attention needed as soon as there is the intention of pregnancy
- influences on fertility (reversible)
- Men and women
- Counseling: Infertility, birth defects, danger to the mother, …
- Mostly dangerous during embryogenesis
CH 7 Pediatric Clinical Development – K. Allegaert
21. The pharmacokinetics of drugs can be profoundly different between children and adults.
Provide an overview of the factors contributing to these differences.
Ontogeny = changes during maturation, i.e. age related drug metabolims
Bodycomposition = age depedent
Large head, growth of lymphoid mass < age 10 and development of genitalia during
puberty
Large amount of body water: Vd decrease till age 2 for hydrophilic drugs
Metabolic capacity
- hepatic maturation: Biotransformation phase 1 or 2
-> drugs more hydrophilic : absent in neonates
CYP3A7: fetal enzyme -> CYP3A4 most prominent in adults
Pharmacogenetics: still need to grow into phenotype, some fetal markers
- No renal clearance -> acculmulation
Strong increase in Clearance <6m
Cox2-inhibitors -> nephrotoxic
- Allometrics (caloric intake): Higher in small animals -> higher dose <2y
GI function: Route dependent bioavailability
Rectal: low conc, large variability, repeated admin -> noise increases
Oral: conc decreases
Integumentary development -> physical bariers
Anaesthesia at early age limits brain development
22. Pediatric clinical pharmacology: the metabolism of drugs (i.e. biotransformation) depends on a
number of co-variables. Discuss these variables and give examples.
Co- variates of metabolism
- Age (ontogeny) -> adjust for enzyme development, but not for size
Cyp-enzymes change: CYP3A7: fetal enzyme & Lung; CYP3A4 most prominent in adults
Dextromethorphan: o-demethylation -> N-demethylation
different metabolites: Dextrorphan acculumates -> Sudden Infant Death Syndrome
Glucuronidation increases first year
- weight
- Polymorphisms: CYP-enzymes or change in receptor efficiency
drug metabolism: maturation -> WT become fast metabolisers; can stay slow metabolizers
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Co-morbidity: type of surgery
Morphine clearance and CYP450 metabolism
Xantine Oxidase, CYP1A2/2C6, NAT2
Environmental: maternal smoking, drinking, comedication
23. What is the objective of the European obligation to make a Pediatric Investigational Plan (PIP)
for all new drugs in development?
Improving the health of children by:
- fascilitating the development and availability of medicines for children
- ensuring that the medicines for use in children are of high quality, ethically researched
and authorised appropriately
- improving the availability of information on the use of medicines in children
Without;
- subjecting the children to unncecessary trials
- delaying the authorisation of medicinal products for adults
CH 8 Guidelines and Regulations – J. Dehoon
24. Discuss the Declaration of Helsinki.
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Informed consent and IND file already excisted
WMA 1964: ethical principles for Medical Research involving human subjects
Revisions have been made over the years: changing environment
For everyone involved: guidelines, not legally binding -> applied to national law
2000: placebo only if no treatment available
Acces of all patients to the best available method (compasionate use)
all results need to be reported
2013: also for storage of human material
25. Give an historic overview of the most important guidelines, regulations and laws concerning
clinical research / clinical trials.
- 1947: Nurenberg Code: Voluntary Informed Consent
No experiments where death or injury is expected, ecept when physician is also at risk
10 basic principles -> basis of curent guidelines and regulations
- 1961: Thalidomide disaster
- 1962: Kefhauver-Harris amendment: IND file needs to be present before going to
humans: Protocol, safety data, efficacy results, side effects, Informed Consent form
- 1964: Declaration of Helsinki: Statement of ethical principles for medical research
involving Human subjects
- 1997: GCP guidelines: Tripartite: Japan, USA and EU
o Technical requirements for registration of pharmaceuticals for human use.
- april 2001: European clinical Trial Directive: guidelines become National law
o Clinical trials involving medicinal products according to GCP
- may 2004: Belgian Law concerning experiments on the human person
o all experiments on humans
26. Belgian law concerning experiments on the human person: what is the difference between an
experiment and a (clinical) trial? Give an overview of the different kinds of experiments and
trials defined within the Belgian law.
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Experiment = trial, study or investigation carried out on the human person with the
aim of developing knowledge particular to the exercise of the Health care profession
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non-commercial exp: sponsor is university, hospital or foundation, owns IP,
concept, execution and results
Clinical trial = any investigation in the human person intended to discover or verify
a clinical, pharmacological and/or pharmacodynamics effects of one or more
IMP, and /or to identify any adverse effects
o non-interventional: normal clinical practice -> extra information
o phase I: Healthy volunteers, without any therapeutic objective
o approval from Competent Authorities
27. Give an overview of the composition and the responsibilities of the Ethics Committee for
clinical research as defined by the Belgian law. Is this in keeping with the requirements as set
forward in the ICH-GCP guideline?
Composition
- institutional review board/ ethical review committee
- 8-15 independent members: 1 lawyer + doctors
- fully recognized: 20 protocols a year
- declare COI -> no voting
- single center: local EC
- multi-center: fully recognized -> chosen by sponsor
Responsibilities
- Relevance of the trial, Risk / benefit analysis
- Protocol; Clinical Investigator Brochure
- Suitability of investigators and staff; Quality of facilities
- Informed Consent Form (ICF); Volunteer payment; Subject recruitment
- Insurance; Financial agreements / contract;
quality criteria according to ICH-GCP -> fully recognized EC
- Only for Clinical trials
- Min 5 members
- Functions and responsibilities are similar
28. Belgian law concerning experiments on the human person: what is the scope of this law? To
what extent is this scope comparable to the scope of the European Directive of 2001?
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All experiment on humans: Drugs, devices, surgery, epidemiological
Born living or able to live
NOT Embryo’s in vitro, biological material, corpses or retrospective studies
for all involved
insurance: no fault needed, causal relationship is sufficient
vulnerable populations
prevent over-volunteering: minimal interval for BE, US and UK, not in EU or GCP
responsibilities of the sponsor: pay EC and CA, insurance, chose EC, apply to CA
o manufacturing, import and distribution of IMP
29. Belgian law concerning experiments on the human person: give an overview of the procedure
one has to follow and the approvals / authorizations which are needed prior to conducting an
interventional clinical trial in Belgium. To what extent is this different for a non-interventional
clinical trial?
Interventional trial
- EudraCT number: on every CTA
- Investigator: submit to local and leading EC -> one written opinion
o Single centre: Local EC 15d
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o Multicentre: leading EC (20d) -> Local EC (5d) -> single opinion (3d)
sponsor: submit CTA to CA -> Tacit approval
o national request: letter, protocol, CIB, IMP dossier and European CTA
o evaluation by CA: quality of IMP and Toxicology
o Tacit approval: 28d, 15d for phase I
o Written approval: Biotechnologicals, AT, gene and cell therapy
start trial: reporting safety, amendment, end of trial, Synopsis CSR
non-interventional: no application to CA and smaller payment to EC
30. Belgian law concerning experiments on the human person: discuss the vulnerable populations
and the precautions taken to protect them in the context of clinical research
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Always written ICF
minors: ICF by parents -> 2 paediatricians in EC
incapable of giving consent: legal representative -> EC: knowledgeable person
emergency: no ICF
prevent professional volunteers
CH9 Good Clinical Practice – B. Van der Taelen
31. What is GCP? Who is GCP for? What are the objectives of implementing ICH-GCP in clinical
research and who benefits from complying with GCP?
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Quality system: A term used for the collection of rules, recommendations and
guidelines on how good clinical research should be performed
Tracability (what), accountability (who) and documentation
Applies to design, conduct and documentation
Everyone: Principal investigator, staff, subject sponsor and Ethical comitee
ICH Regulatory groups and industry in US, EU and Japan -> guideline E6: GCP
o Safeguard Safety, efficacy and quality
o Allow global acceptance
o Reduce number of humans and animals used
o Allow rapis approval and availability
Everyone: Subject (safety), investigator (credibility) and sponsor (international
approval, valid data, quality assurance), public reassurance
32. What is ICH? What are the objectives of it and which topics are covered by ICH?
International Conference on Harmonization
Regulatory groups and industry from US, EU and Japan
Objectives
- Safety: Safeguard Safety, efficacy and quality
- Globalisation: Allow global acceptance
- Economy: Reduce number of humans and animals used
- Timeline: Allow rapis approval and availability
Topics:
- Quality: Chemical and Pharmaceutical Quality Assurance
- Safety: in-vitro and in-vivo pre-clinical testing
- Efficacy (GCP)
- Multidisciplinary: electronical standards, standardization of medical terminology
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33. What is an informed consent form? Give an overview of the informed consent process for
participation in a clinical study? What is the historical origin of this procedure
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Information pages : Describes the rights of a study participant: details about the
study to start the communication
signature page: subject and informer, personally date
Voluntary, Before any study has taken place
Explain study, use simple words, answer questions, give time, sign, provide copy of
ICF
Origin: post-world war II crime trials for unethical medical experimentation in
Nurenberg
34. What is an IRB / IEC? What are the functions, composition and responsibilities of this
committee? Are there any differences with respect to function, composition and
responsibilities of an IRB between the GCP guideline and the Belgian law of May 2004?
Institutional review board / Independent ethics committee
- Protection of rights, safety and well being of human subjects involved in the trial,
continuously review
Functions: minimize risks and follow-up conduct of trial
Composition: Indepentent from investigator with sufficient qualifications and experience
 3 IRB members, non-scientific member and independent member drom institution
Responsibilities:
- Review a proposed trial and continue review
- Review Investigator
- Especially when involving vulnerable subjects
- Announced meetings and adequate records
IRB according too Belgial Law May 2004
- Experiments (not just trials) on humans: drugs, surgery devices, …
- Approved by IRB or IEC
- Composition: independent body 8-15 members: doctors, min 1 lawyer, declare COI
35. What are the differences between monitoring, auditing and inspection of a clinical study?
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Quality assurance: planned and systematic actions to confirm compliance with GCP,
based on SOP
- Audit: retroactive quality assurance -> ensure quality of product and process
= A systematic and independent examination of trial related activities and documents
to determine whether the evaluated trial related activities were conducted, and the data
wererecorded, analysed and accurately reported according to the protocol, sponsor’s
SOPs,GCP and the applicable regulatory requirement(s).
- Differs from Monitoring: independent observer covers entire study up to that point (once)
- Inspection: official review of documents, facilities and records by regulatory authorities
o Routine, for-cause or pre-approval
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Chapter 10: Drugs and society – I. Spriet
Pharmacopeia: Official handbook with standards for analysis of drugs, all products should
comply, mentioned on leaflet
Unmet Medical need: No alternative available
Drug: substance presented with therapeutic or prophylactic characteristics
Ex tempore preparations: Is prepared according to receipt in a pharmacy for an individual
patient
Completely individual, standardized or mixture of commercially available products
All products should fulfill quality standards
Physician (prescription & receipt -> Pharmacist (preparation and distribution)
36. Discuss: the nomenclature of drugs.
Chemicale name: based on chemical structure
- Para-acetoaminophepol or Acety-salisylic acid
Generic name: international nonproprietary name (refers to API)
- Paracetamol or Asprin
- Easy to recognize: minimanl risk of mistakes, not too long, valid in different languages
- Often refer to the pharmavological class (-mab, -pril, …)
Trade name: different names within and between countries
- Daphalgan or Aspro
- Publishes in WHO Bulletin
Anatomic Therapeutic Chemical Classification: 5 Levels by WHO
- Associated with daily defined dose
- Based on functioning (anti-infectives -> antibacterial -> penicilins)
37. Discuss the difference between “off label” and “unlicensed” use of drugs and illustrate with an
example.
OFF label: used in other indications then approved:
- IV Ig in Staphylococal septic Shock
- Retuximab (anti-CD20) in idiopathic thrombocytopenia purpura
Unlicensed: use in different patient population, different dose, other routes of administration
without taking into account any CI
- E.g. use of enoxaparin (LMWH) as thrombo-prophylaxisin neurosurgical patients despite
contra-indication (becauseof risk of bleeding) in package insert
Why? Use in children, registration not attractive for company, application not researched,
sometimes standard practice
38. Discuss the different aspects and the importance of cold chain management. Give a real life
example.
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Management of guaranteeing the adequate storage of drugs, even if they have to
be kept at special temperatures
Original product: production, transport and storage
Alarm system ( on fridge, freezers) emergency electrical supply
After reconstitution and dissolution
o Antibiotics and injectable drugs (stability and sterility)
Emergency vehicles: cold chain has been broken
o exposed to vibrations, light, heat
o lose effectiveness: replace every 2 months
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39. What is “polypharmacy”? What are the dangers associated with it? (also explain in the context
of transmural care).
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Concomitant use of multiple therapies (>5)
Old age, associated/multiple pathologies, prescribing cascade
Interactions, less compliance and more side effects
40. What is seamless or transmural care? What are the barriers associated with it,
especially in Belgium?
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Efficient transfer of information associated with hospitalization
Admission: Adequate drug history
Discharge: which should be continued, added, …
Hospital pharmacy: up to 3 days after discharge
Substitution: wrong or no substitution, double therapy
41. Discuss the financial “life cycle” of drugs including the implications for the pharmaceutical
company?
Company: Price setting
- Licensing (ministry of health care)
- Original Price setting (ministry of economic affairs)
- Basis for Reimbursement
- Expiry of patent
o No generic: decrease with 15% after 12y
o Generic available: decrease with 30%, after 2, 4 and 12 years even further
decrease -> reference reimbursement
- Eventually >40% lower
Government: reimbursement: Annual review of budget, Clawback and sparefunding from Pharmaceutical companies
Patient: Non-reimbursed vs reimbursed; Personal contribution?
42. Give an overview of the reimbursement of drugs for ambulatory patients, depending on the
“category” and “chapter” they are in (provide examples)
Category: percentage of reimbursement based on importance
A. Lifesaving
100%
ex Insulin, cytostatics
B. Therapeutic Important drugs 75%
ex antibiotics, antiHT
C. Symptomatic treatment
50-40-20%
ex anti-conception, ASA
D. Not reimbursed
- Ministry of Health Care and Social Affairs (advice from committee of reimbursement)
Chapter: criteria for reimbursement based on indication
I.
For all indications
ex Antibiotics, Insulin
all cat
II.
Indications based on IBM
ex PPI, lipid lowering drugs
cat B & C
III.
Infusion fluids
ex parenteral nutrition
cat B
IV.
Specific indications
ex certain cytostatics and antifungals
- A priori control: after approval by mutuality
- Bis: drugs available abroad
cat A & B
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43. Give an overview of the existing options in Belgium to make drugs available to patients free of
charge. What are the restrictions and requirements?
Compassionate use
- Chronical or life threatening illness
- Centralized procedure, if no alternative approved in Be
- Ongoing registration or Clinical Trial
- Company should inform Government and local EC
- Physician can apply for CU
Medical Need Program
- Same principles as CU
- Under approval for other indications
- Labeled as “MNP – Can not be sold”
Medical Samples
- Under approval and available
- At most smallest package available
- Labeled as “free sample – Can not be sold”
- Not for narcotics, psychotropic, or it containing isotretinoin
- Physician: max amount, should apply
- Company: document and annual report
Chapter 11: Registration and reimbursement – M Casteels
FAGG: Federal Agency for Medicines and Health products, ensure quality, safety and efficacy
MAA: Market Authorization Application
CMA: conditional marketing authorization
CHMP: committee for Medicinal Products for Human use
EPAR: European Public Assessment Report
SmPC: Summary of Product Characteristics
CTG: comité voor tegemoetkoming van Geneesmiddelen
44. Which are the most important procedures available in Europe for the registration of new
drugs? Which are the pros and cons of each procedure?
Central procedure
- 1 application to EMA
o evaluation by CHMP -> EPAR & gives final SmPC
o commitments, follow-up questions, outstanding issues, RMP
- 1 MA, 1 Tradename
- Compulsory: Advanced technologies, Diabetes, HIV, Autoimmune diseases, Orphan
drugs, neurodegenerative diseases, cancer,…
- Pro: 1 application, 1 approval, consensus and 10y exclusivity
- Con: All-or-nothing, 1 tradename, limited time for translation, rapporteurs selected by
CHMP (2 Member states)
MRP= mutual recognition procedure
- National phase: application -> MA -> Assessment report
- Mutual recognition: validation -> recognition -> National authorization
- Pro: choose the reference MS, earlier commercialization , different Trade names,
withdraw in one MS if concerns, still valid in others
- Con: individual evaluation per MS (more objections), not all countries accept
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DCP = decentralized procedure: No MA available yet, similar to MRP
45. Give an overview of the reimbursement procedure for drugs in Belgium. What is the role of
the commission for the reimbursement of drugs (CTG/CRM) in Belgium? What is the role of
the different ministries?
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-
Reimbursement after MA by Sponsor (within SmPC)
Sponsor asks to admit, modify or cancel reimbursement
Maximum price (M. of Economic Affairs)
Apply for reimbursement with CTG -> motivated advice based on Motivation File
Reimbursement (M. Social Affairs) based on Class and Chapter
o positive decision: inform Inspector of Finances and Ministry of Budget
o Company notified within 180 Days
o Transparency: Declare COI
Integrate Evidence Based Medicine: safety, efficacy, added value, pharmacoeconomic
arguments
Possibility for revision: Follow-up, Group or individual
Change of reference reimbursement after patent expires
does not take into account: Real-life data, Rare AE, competitors, benefit/risk
Chapter 12: the medical department – D. Vander Mijnsbrugge
Attrition: High developmental failure, low discovery yield -> Interactions, manufactureing,
side effects, efficacy, safety, dosing, lack of benefit.
46. Provide an overview of the tasks of a medical department within a pharmaceutical company.
Research and Development – Global
- Input on protocol development based on regulatory feedback
o Endpoints, design, comparators, feasibility, …
- Select clinical sites : Infrastructure, knowledge, Interest, potential, …
o follow up: compliance with GCP and protocol
Regulatory – European
- Centralized procedure
- Mutual Recognition Procedure
- Coordinate local activities: answer questions, timely applications to Reg.Auth.
Access – Local
- Reimbursement after registration
o Maximum price (M. of Economic Affairs)
o Apply for reimbursement with CTG -> motivated advice
o Individual revision: CTG decides when and what elements
o Reimbursement (M. Social Affairs)
- Evidence based: safety, efficacy, added value, pharmacoeconomic arguments
Commercialization
- Life cycle of drugs: New Indications, dosing, formulations,..
- Maintain registration: renewal, Pharmacovigilance, keeping registration up-to-date
o Periodic safety update reports by Rapporteur MS
- Maintain reimbursement: observational studies, post reimbursement commitment , monitor
available evidence and present when needed
- Medical information: strictly regulated -> Label, Scientifically accurate
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Chapter 13: pharmacovigilance
Pharmacovigilance: monitor safety, reduce risks and increase benefits of medicinal products
RMP: Risk Management Plan
PSUR: Periodic Safety Update report
47. Pharmacovigilance (pre-registration): discuss the causality assessment of an adverse event
taking place during a clinical trial.
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-
-
Determine the likelihood that the treatment is the cause of the ADE (case study)
Important to determine Benefit/Risk ratio
Is it possible? (previous knowledge) Dit it cause the AE? (assessment)
o Global introspection: Based on clinical judgement
o Algorithms: calculate likelihood based on soecific questions and scoring (rare)
o Bayesian approach: probability based on prior knowledge or specific data
(posterior)
Multicausal: Drug (dose, interactions,…), person (age, sex, diseases,…), external factors
Limited scientific value -> need for further research
Important parameters
o Time of reaction: reaction follows administration
o Positive dechalenge: improvement in reaction when drug is withdrawn
 Not for irreversible reactions
o Positive rechalenge: Event reoccurs, mostly accidental, when AE is objectifiable
 Benefit needs to outweigh the risks
Performed by PI, can include DSMB
48. Pharmacovigilance: what is the difference between an adverse event and an adverse drug
reaction? (take the definitions in the Belgian legislation into account). When will an adverse
event or an adverse drug reaction be considered “serious”?
ADR: all untoward and unintended responses to an IMP or to an experiment and, when
an investigational product is concerned, related to any dose administered
ADE: any untoward medical occurrence in a patient or subject of the treated group during
an experiment, and which does not necessarily have a causal relationship with this
treatment
Serious: Death, life-threatening, hospitalisation, disability or congenital abnormality
49. Discuss: Data Safety Monitoring Board.
DSMB
- Independent experts that follow-up Safety, progress and efficacy endpoints
o Clinicians, Biostatistition, other experts: scientist, EC, parents,…
- Gives advice on modifications, continuation and termination
- When? In potential risk: large multicentre trials, severe morbidity as endpoint, …
- What? Safeguard safety, study ADR, follow-up inclusion criteria, detect protocol
violations, edit DSMP, detect high rates of drop out or exclusion, …
- Max information out of study
- Interim analysis of potential risks, unblended
o Evaluate efficacy, safety, detect potential bias, statistical analysis
Data safety monitoring plan
- Contains process to be followed to guarantee safety and well-being of participants
- Monitor progression and safety, report any AE, ensure accuracy and conpliance
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50. Define some important limitations of the safety evaluation of a drug (i.e. pharmacovigilance)
during (1) the premarketing period and (2) after bringing the drug onto the market
Premarketing Period
- Rechallenge and causality assessment not always possible
- Very rare side effects are difficult to detect in a short time frame
- The selection of subjects sample is very restricted: limited view & homogeneous
 contrast with the real situation (where everybody uses it with other medication)
Postmarketing Period
- collecting data: sufficient information needs to reach the company and authority
o mutual responsibility
- no RCT possible, mostly case studies (observational)
- difficult to prove causal relationship
- underreported
- unbalanced and incomplete reports
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